ABSTRACT Pancreatic cancer (PC) is an extremely aggressive malignancy with one of the worst prognoses of all cancers. With marked resistance to chemo- and radiotherapies, surgery is the only curative option. In patients with localized disease, complete surgical resection provides five-year survival rate of 30-75%. However, >80% of patients are diagnosed with unresectable primary tumors and/or distant metastasis. The major cause for late clinical presentation, and the resulting high mortality, is the lack of a conclusive non-invasive early diagnostic test. Multiple concerns exist regarding the unapproved use of CA19-9 (a diagnostic test for GI malignancies) to help diagnose PC. These include its non-specificity, elevation in benign diseases, and absence in 30-35% of the African American population; which underscore the need for new diagnostic tests/prognostic markers for GI malignancies ? especially one that can confirm PC early. A widely distributable technology, with a highly specific and sensitive diagnostic ability to discriminate real disease (resectable neoplasms) from confounding high risk groups [pancreatitis, benign pathologies (acute biliary obstruction, common bile duct stone, cholecithiasis), and non-malignant benign cystic neoplasms (serous pancreatic cystic neoplasms)] could change the fate of PC patients. A vast series of cell-line, genome-wide, and tissue-based studies have elucidated differential expression of MUC5AC and MUC4 in PC in comparison to pancreatitis and various benign pathologies. However, the complexity of their structure and low serum levels limited their development as diagnostic markers for pancreatic cancer. In our preliminary studies, we developed an immunoassay to detect these markers and validated their diagnostic potential in a panel of patient serum samples. These mucins emerged as highly sensitive and specific biomarkers for differentiating pancreatic cancer cases from controls. MUC5AC efficiently differentiated early pancreatic cancer from healthy controls [83%/80% sensitive (SN)/specific (SP)] or benign [67%/87% SN/SP], and chronic pancreatitis [(83%/77% SN/SP] groups. Further, a CA19-9 and MUC5AC combination significantly (<0?001) improved the diagnostic accuracy of CA19-9 in differentiating resectable cases from controls. Together CA19-9, MUC5AC and MUC4 differentiated PC cancer from controls with absolute specificity. Based on preliminary evidence, we hypothesize that the mucin core proteins (MUC5AC and MUC4) in combination with CA19-9 create a PC-specific biomarker panel for early detection of pancreatic cancer. Development of the non-invasive test for reproducible and economical detection of PC in the at-risk population will enable early diagnosis for PC treatment. To test this hypothesis, we propose to optimize (CA19.9, MUC5AC, and MUC4) measurement with a master calibrator that contains the analytes. Clinical validation will be performed using a blinded serum reference set from Early Detection Research Network that includes cases from the high- risk groups. Overall, the successful SBIR Fast-track project would result in a commercial grade PC-specific test that would improve upon CA19-9 for early detection and diagnosis of pancreatic cancer.